DESCRIPTION (adapted from application abstract): Herpes simplex viruses type 1 (HSV-1) are ubiquitous human pathogens. HSV-2 is a major cause of genital herpes and one of the most frequent sexually transmitted diseases. The worldwide prevalence of genital HSV-2 continues to increase; approximately 22% of adults are infected with HSV-2 representing a 31% increase over the last decade. Cellular immune defects are more closely associated with severe HSV disease than humoral immune defects pointing to a key role of HSV-specific T cells in the control and resolution of disease. Because of the high seropositivity rate of HSV-1 and HSV-2 among most populations, the occurrence of acquired resistance to HSV was doubted. However, in a systematic study of T cell responses to HSV in HSV-1 and -2 seronegative individuals with no prior history of HSV disease, we have identified 3 of 19 individuals with persistent HSV-specific cytotoxic T lymphocyte (CTL) and lymphoproliferative (LP) responses (termed immune seronegatives, IS). We hypothesize that in a subgroup of individuals, HSV-specific T cell responses are acquired by previous exposure to HSV and that such responses resist infection by HSV. These individuals may be the ones who offer insight into defining what constitutes protective immunity to HSV. Specific Aim #1 will characterize the systemic CD4+ and CD8+ T cell responses to HSV in IS. Protective immunity requires long-term memory responses, and thus we address the question: Do these T cell responses persist or are they transient? Are the HSV antigens recognized by HSV-specific T cells from IS different from those observed in individuals with recurrent HSV disease? Specific Aim #2 will determine if IS are infected with HSV-1 or -2 in the absence of seroconversion. Highly sensitive PCR-based shedding studies will be employed to detect if HSV-1 or -2 are shed mucosally in these persons. Specific Aim #3 will explore if genital and/or oral mucosa sites contain T cells and antibodies specific for HSV in IS. Is there an increase in the frequency of HSV-specific T cells and antibody-secreting cells from the site of viral exposure? Delineating immune responses in person with acquired immunity or those with no history of HSV infection will provide insight into the immunobiology of HSV infection and acquisition and assist in the rational design of protective vaccines.